Design, Synthesis, and Structure–Activity Relationships of 3,4,5‐Trisubstituted 4,5‐Dihydro‐1,2,4‐oxadiazoles as TGR5 Agonists

Abstract

Given its role in the mediation of energy and glucose homeostasis, the G‐protein‐coupled bile acid receptor 1 (TGR5) is considered a potential target for the treatment of type 2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand‐based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5‐trisubstituted 4,5‐dihydro‐1,2,4‐oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5‐dihydro‐1,2,4‐oxadiazoles and extensive structure–activity relationship studies are reported herein. Compound (R)‐54 n, the structure of which was determined by single‐crystal X‐ray diffraction and quantum chemical solid‐state TDDFT‐ECD calculations, showed the best potency, with an EC50 value of 1.4 nM toward hTGR5. Its favorable properties in vitro warrant further investigation.

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

“…4 ). TDDFT-ECD calculation was proved an efficient method to determine the absolute configuration of separated stereoisomers of bioactive synthetic [ 19 ] and natural derivatives [ 20 – 21 ] on the basis of their HPLC-ECD spectra.…”

Furanolabdanoid–based 1,2,4‐oxadiazoles: Synthesis and cytotoxic activity

“…[24] The synthesis of a biheterocyclic system of furanyl – 1,2,4‐oxadiazole type was still unexplored in spite of that the furan ring has been recognized as one of the important frameworks due to its occurrence in natural and synthetic bioactive compounds . At the some time, a group of 3‐furanyl‐4,5‐dihydro‐1,2,4‐oxadiazoles was synthesized and characterized as TGR5 agonists . Therefore, there are considerable interest in a targeted preparation and investigation of labdanoids, containing a furanyl – 1,2,4‐oxadiazolyl substituent in the molecules and evaluation of their cytotoxic activity.…”

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

“…All compounds were synthesized upon the reaction of the appropriate parent p-pyridine amidoxime 1 [58], ethanone oxime 14 [59] and aldoxime 21 [60] with the corresponding isocyanates 2-7 in good to excellent yields (Scheme 1). When the reactions have been performed at room temperature the yields were poor for most of the products.…”